Novel 19-oxygenated-b-nor-androstanes



United States Patent 3,336,302 NOVEL 19-0XYGENATED-B-NOR-ANDROSTANESKenneth G. Holden, Stratford, N.J., and James F. Kerwin,

Broomall, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvama No Drawing. Filed June1, 1965, Ser. No. 460,573 13 Claims. (Cl. 260--239.55)

This application is a continuation in part of copending Ser. No.440,284, filed Mar. 16, 1965, now US. Patent 3,284,505, which is in turna continuation in part of copending Ser. No. 358,417, filed Apr. 8,1964, now abandoned.

This invention relates to novel -19-nor-B-nortestosterones as well as tomethods and intermediates for preparing same. The19-nor-B-nortestosterones of this invention have utility as medicinalagents particularly having depressant or antiandrogenic activity as wellas intermediates for preparing other l9-nor-B-norsteroid medicinalagents having similar activities.

More specifically the end products of this invention are illustrated bythe following structural formula:

Formula I in which R represents lower alkyl such as methyl or ethyl,ethynyl, and hydrogen; and X represents hydrogen, acetoxy, hydroxy orhalo such as fluoro, brorno or chloro. As usual in the steroid art theacyl derivatives of these compounds can be optionally prepared by artrecognized methods especially those acylates derived from carboxylicacids having a maximum of 8 carbon atoms preferably acetyl. Also, theB-nortestosterones (Formula I) in which R is hydrogen can be optionallyconverted to their cyclohexenyl, cyclopentyl or tetrahydropyranyl etherderivatives. The compounds of this invention are prepared as describedin the following reaction sequence using a 3,19-dihydro-androst--en-l7one [(I), J. Kalvoda, et al., Helv. Acta., 46, 1361 (1963)] or itsacylate derivative as starting material.

AcOCH:

II III AcOCHa 0 A00 CH2 0 a L A00 =0 C 05H A00 IV V AGO CH2 O HO OH: O Ip A00 OH VI VII HOCH: OH I OH HOOC I --9 HO O VIII IX OH OH U "R X XI Inthis reaction sequence Ac represents any art recognized acyl group suchas those described hereabove. A-cetyl is most convenient. R representslower alkyl or alkynyl.

This reaction sequence essentially comprises contracting the B ring of a19-functionalized steroid, degrading the 19-function to give the19-nor-B-norandrost-l7-one then inserting the desired function at C17.This general reaction can be accomplished by several syntheticvariations of this idea as will be obvious to those skilled in the artbut is illustrated by the sequences I- XI and I- VII XVI describedherein.

3,8,l9-diacetoxy-androst-S-en-17-one (I) is oxidized to the oxido orepoxy group at C-6,7 using standard mild oxidizing agents such as aperacid, for example, perbenzoic acid or m-chl-oroperbenzoic acid in aninert organic solvent in which the reactants are substantially solubleat moderate temperatures such as at about room temperature or lower. Theresulting 5,6-epoxy isomeric mixture (II) is oxidized gently at C-5,6 tothe 5a-hydroxy-6-keto compound (III) usuallywith chromic acid oranhydride in an aqueous-organic solvent mixture at temperatures lowerthan about 4050 C.

The dione (III) is oxidized to the 5,6-seco derivative (IV) using a mildoxidizing agent such as a perbenzoic acid in a suitable, inert organicsolvent at temperatures under room temperature (30 C.). The secocompound is cyclized using benzoyl chloride-pyridine to the 5,6- lactonewhich is degraded by pyrolysis to the important intermediate3B,19-dihydroxy-B-norandrost-S-en-17-0ne (VII).This synthetic method ofdegrading ring B is generally similar to those reported by K. Tanabe etal., US. Patent No. 3,061,635.

The important 17a-alkyl derivatives of this invention are prepared byreacting VII or its O-acylate preferably acetate derivative with a loweralkyl metal compound such as methyl or ethyl lithium or with thecorresponding Grignard reagents such as lower alkyl magnesium bromide,iodide or chlorides in an inert solvent such as tetrahydrofuran or ethermost conveniently at reflux temperature to give a3,8,175,19-trihydroxy-l7a-alkyl-B-norandrost-S-ene (VIII) which isoxidized at C19 with chromic acid in aqueous acetone at about -5 C. tothe IO-carboxy-B- nor compound (IX) which is then decarboxylated usuallyby pyrolysis. The decarboxylation may be run by pyrolysis under basicconditions such as in a tertiary base, i.e., pyridine, to give theimportant l9-n0r-5(l0)ene intermediate (X). This compound (X) isrearranged usually by reaction with sodium methoXide-methanol into thedesired 17a-alkyl-19-nor-B-nortestosterone. Alternatively, thedecarboxylation can be carried out under acid conditions, such as usingGirard T reagent. In this case the desired 19-nor-B-nor-4-androstane isobtained directly (i.e., XII- XIV below).

The testosterone compounds, i.e., those in which R is hydrogen, areprepared from 35,19-dihydroxy-B-norandrost--en-l7-one (VII) as follows:

VII is oxidized using standard chromic acid in acetone in the cold asdescribed to form the 3-one-10-carboxy compound which is thendecarboxylated by heating at reflux in pyridine to the 5 (10)ene (XIII).This compound is rearranged with sodium methoxide-methanol to theimportant intermediate l9-nor-B-norandr0st-4-ene-3,17-dione (XIV).

XIV is reduced to convert the keto groups at C3 and 0-17 into hydroxylsusing lithium aluminum hydride in ether, tetrahydrofuran or mixturesthereof at from room to reflux temperature. Reaction of the resulting313,175-dihydroxy-19-nor-B-norandrost-4-ene (XV) with2,3-dichloro-5,6-dicyanobenzoquinone in dioxane gives the desiredl9-nor-B-nortestosterone (XVI).

The compounds of Formula I in which X is other than hydrogen areprepared by reactions on the 19-nor-B-nortestosterone or its 4,5-epoxidederivative directly, such as sulfuryl chloride in organic solvent on thetestosterone or hydrogen halide on the epoxide which is in turn preparedfrom the testosterone parent using perbenzoic acid.

The l7-alkyl-B-nortestosterones possess a tendency to dehydrate atposition 17 under direct treatment and are, therefore, preparedindirectly as noted in the examples.

The acyl derivatives of the 19-nor-B-nortestosterones of this inventionare prepared by reacting the testosterone parent with an acyl halide oranhydride usually in excess in the presence of base with an organicsolvent optionally present. The 19-nor-B-nortestosterone acylates areusually prepared with an excess of acyl anhydride in pyridine at roomtemperature or with slight warming. Quenching in water gives the desired17-acylate. The 17oc-a1kyl-19- nor-B-nortestosterone acylates areprepared using more vigorous conditions such as at reflux using anexcess of the anhydride. Generally speaking the carbon content of suchO-acylate derivatives will not exceed 12.

The tetrahydropyranyl ether derivatives are prepared by reacting thetestosterones of Formula 1 with dihydropyrane in benzene in the presenceof p-toluenesulfonic acid. The cyclohexenyl and cyclopentenyl ethers areprepared by reacting the same compounds with cyclohexanone oreyclopentanone dimethyl acetate in the presence of p-toluenesulfonicacid. The cyclopentenylether of B-nor-19-nortestosterone is aparticularly potent antiandrogenic agent.

The l7u-alkyl and unsubstituted l9-nor-B-nortestosterones of thisinvention are active central nervous system depressant andantiandrogenic agents. The other compounds disclosed herein have utilityas intermediates for preparing these 19-nor-B-nortestosteronederivatives.

The compounds covered in this application are characterized by havingoxygenated carbon atoms at position 19, i.e., such as a hydroxymethyleneor a carboxy gr-oup substituted on a B-norandrostane nucleus. All ofthese compounds are of use as intermediates for preparing l9-nor-B-nortestosterone derivatives having antiandrogenic activity. The19-oxygenated compounds claimed here have also been found to have potentantiandrogenic and antianabolic activity with little C.N.S. depressantactivity.

The compounds especially active as antiandrogenic compounds are thosepossessing the following basic structural formula:

/ CH3 H Derivatives of these compounds obvious to those skilled in theart, especially those as described herein such as O-acyl derivatives,4-substituted compounds or ether derivatives are equivalent to theseparent compounds.

Among the processes of the invention as described hereabove the processof oxidation of the l9-hydroxymethylene-B-norandrostane to form thel9-carboxy-B-norandrostane using the Jones reagent is of particularimportance. The oxidation is carried out in a ketonic solvent such asacetone or methyl ethyl ketone using standard Jones reagent (chromicacid in dilute sulfuric acid) usually in the cold such as from about 010C. Other variations in the reaction conditions of this process will beapparent to those skilled in the art from Bowden et al., J. Chem. Soc.,1946, 39, or Steroids, Fieser, 1959, pp. 52 and 224.

Also part of this invention is the method of decarboxylation ofl9-carboxy-B-norandrostanes comprising pyrolysis usually under basicconditions such as heating usually at reflux temperature in a tertiaryamine such as pyridine, lutidine, etc. for about 1-4 hours. Theresulting compound is the A -B-norandrostene which is rearranged bybrief treatment with an inorganic acid such as hydrochloric acid or amedium strength base such as sodium methoxide-methanol or methanolicsodium hydroxide with mild heat such as on the steam bath for up to 30minutes. Alternatively the decarboxylation can be carried out undersimilar mild acid conditions.

It will be obvious to those skilled in the steroid art that variationsof this invention can be made without departing from the nub, i.e., the19-nor-B-nortestosterone structure, as described above. For example, thestarting material can contain inert substituents such as a 160: or 166-methyl group or alternative but equivalent reaction conditions known tothe art for converting discrete moieties as desired may be used. Suchare meant to be included in this invention. The following examples aredesigned only to illustrate further the practice of this invention.

EXAMPLE 1 To a solution of 43.6 g. of 3p,19-diacetoxyandrost-5-en-17-one (I, Ac=acetyl) [see I. Kalvoda et al., Helv. Chim. Acta., 46,1361 (1963)] in 300 ml. of chloroform is added 25.8 g. ofm-chloroperbenzoic acid in 150 ml. of chloroform. The addition iscarried out with stirring so that the temperature of the reactionmixture is maintained at 25-30 C. After addition is complete thereaction mixture is allowed to stand for three hours and is then washedwith aqueous sodium sulfite and then with aqueous sodium carbonatesolution. Drying and evaporation of the chloroform phase gives a residuewhich is crystallized from acetone-hexane to give 3 ,8,19-diacetoxy-5,6-epoxyandrostan-17-one (II), M.P. 128129 C.

To a stirred solution of 3B,19-diacetoxy-5,6-epoxyandrostan-17-one (II,42 g.) in 1200 ml. of methylethylketone is added aqueous chromic acid(50g. of chromium trioxide in 100 ml. of water) at such a rate that thetemperature of the reaction mixture does not exceed 40 C. After additionis complete the reaction mixture is maintained at 40 C. for one hour andis then poured into 2500 ml. of Water. Extraction with methylenechloride followed by drying and evaporation of the organic extractsgives crude 3 9,19-diacetoxy-Sa-hydroxyandrostan-6,17-dione (III) whichmay be used in the next step without purification.

To a solution 42 g. of the crude dione in 200 ml. of chloroform is added50 g. of m-chloroperbenzoic acid in 350 ml. of chloroform. The additionis carried out slowly with stirring so that the reaction temperaturedoes not rise above 30 C. After stirring at room temperature for 24hours the reaction mixture is washed with aque ous sodium sulfitesolution (500 ml.) and then with 5% aqueous sodium bicarbonate solution(700 ml.). The sodium bicarbonate phase is acidified with phosphoricacid and extracted with chloroform to give, after drying and evaporationof the chloroform a mixture of m-chlorobenzoic acid and3B,19-diacetoxy-5,17-dioxo-5,6-secoandrostan-6-oic acid (IV).

The above mixture is dissolved in 150 ml. of pyridine and treated with50 ml. of benzoyl chloride with cooling. After standing for 24 hours atroom temperature the reaction mixture is poured into 1500 ml. of waterand extracted with methylene chloride. After washing with cold aqueousphosphoric acid and sodium carbonate solutions the methylene chlorideextracts are combined, dried and evaporated. The residue may becrystallized from ether to give 35,l9-diacetoxy-5fl-hydroxy-17-oxo-B-norandrostan-6-oic acid 5,6 lactone [(V), M.P. 170 C. (dec.)], or moreconveniently, the crude residue is heated at 190 C., under a nitrogenatmosphere for ten minutes to give crude3,8,l9-diacetoxy-B-norandrost-S- ene-17-one (VI) which is dissolved inethanol containing excess aqueous potassium hydroxide solution andheated at reflux for two hours. The cooled reaction mixture is pouredinto water and extracted with methylene chloride to give, after dryingand evaporation of the methylene chloride phase, 815 g. of a residue.This material is dissolved in benzene/methylene chloride (9:1) andchromatographed on 125 g. of alumina (III, Woelm). Elution withmethylene chloride and methylene chloride-methanol mixtures gives3p,19-dihydroxy-B-norandrost-5-en- 17-one (VII) which, afterrecrystallization from acetonehexane, melts at 148-150 C.

EXAMPLE 2 A solution of 3.0 g. of 3B,19-dihydroxy-B-norandrost-5-en-17-one (VII, Example 1) in ml. of tetrahydro furan is treated with7.0 g. of methyl lithium. The reaction mixture is heated at reflux undera nitrogen atmosphere for two hours and is then cooled and treated withmethanol to destroy excess methyl lithium and the resulting mixture isthen poured into water and extracted with methylene chloride to give,after drying and evaporation of the solvent, 35,173,19-trihydroxy-17a-methyl- B-norandrost-S-ene (VIII).

The crude triol (VII) is dissolved in 35 ml. of acetone and added to asolution of 12 ml. of standard chromic acid reagent (26.7 g. of chromiumtrioxide and 23 ml. of concentrated sulfuric acid diluted to 100 ml.with water) in 40 ml. of acetone at 0 C. After stirring for six minutesthe reaction mixture is poured into water and extracted with methylenechloride. The methylene chloride extracts are combined and extractedwith aqueous sodium bicarbonate solution which on acidification andextraction with methylene chloride yields l7fl-hydroxy-17ot-methyl-3-oxo-B-norandrost-5-en-19-oic acid (IX) after drying and evaporation ofthe solvent.

The crude acid (IX) is dissolved in pyridine and heated at reflux forone hour. The pyridine is evaporated at reduced pressure to leave aresidue at 17p-hydr0xy- 17a-methyl-l9-nor-B-11orandrost-5 (10) -en-3-one(X).

The ketone (X) is dissolved in 50 ml. of methanol containing 0.1 g. ofsodium methoxide then heated at reflux for one hour. The cooled reactionmixture is poured into Water and extracted with methylene chloride.Drying and evaporation of the methylene chloride extracts gives aresidue which is purified by column chromatography on alumina followedby crystallization from acetonehexane to giveNix-methyl-19-nor-B-nortestosterone (XI), M.P.150-151" C.

XI (500 mg.) in 25 ml. of acetic anhydride is heated at reflux overnightthen quenched in water to give the acetate derivative.

Substitution of ethyl lithium for methyl lithium in the reactiondescribed above gives 17a-ethyl-l9-nor-B- nortestosterone.

Substitution of ethynyl magnesium bromide for methyl lithium and usingthe diacetate derivative of 3/3,19-dihydroxy-B-norandrost-5-en-17-one intetrahydrofuran, above, gives 17a-ethynyl-l9-nor-B-nortestosterone.

EXAMPLE 3 Oxidation of 4.0 g. of 3,8,19-dihydroxy-B-norandrost-5-en-17-one (VII) by the method used for3fi,17B,19-trihydroxy-l7a-methyl-B-norandrost-5-ene (VIII) gives 3.23 g.of crude 3,l7-dioxo-B-norandrost-5-en-19-oic acid (XII) which isdecarboxylated and rearranged as described for the170t-I1'1CthYl-17/3-hYdI'OXY series to give 19-nor-B-norandrost-4-ene-3,17-dione (XIV), M.P. 153 C., via19-nor-B-norandrost-5(10)ene-3,17-dione (XIII).

Alternatively, XII is reacted with Girard T reagent [Gardi et al., Gazz.Chim. Ital., 93, 514 (1963)] to give the intermediate hydrazone which isthen decomposed using mineral acid at room temperature (see Example 7).

To a stirred suspension of 1.05 g. of lithium aluminum hydride in 75 ml.of ether is added a solution of 1.6 g. of the dione (XIV) in 35 ml. oftetrahydrofuran. The addition is carried out at room temperature, withstirring over a 15 minute period. The reaction mixture is then heated toreflux for two hours, cooled, treated with 5 m1. of water and filtered.Evaporation of the filtrate gives a residue of3,6,17fi-dihydroxy-l9-nor-B-norandrost-4-ene (XV).

The crude diol (XV) is dissolved in 50 ml. of dioxane to which is addeda solution of 2.5 g. of 2,3-dichloro-5,6-

dicyanobenzoquinone in 50 ml. of dioxane. After eight hours at roomtemperature the precipitated hydroquinone is removed by filtration andthe filtrate is evaporated to a residue which is dissolved in methylenechloride and passed through a column of 30 g. of alumina (III, Woelm).Evaporation of the eluate gives a residue which after recrystallizationfrom acetone-hexane melts at 135- 136 C. and is 19-nor-B-nortestosterone(XVI).

This material (200 mg.) is dissolved in 2 ml. of pyridine and reactedwith 1 ml. of acetic anhydride overnight at room temperature. Quenchingin water gives the acetate derivative, M.P. 145l46 C. afterrecrystallization from acetone-hexane.

The l-cyclohexenyl or l-cyclopentenyl ethers are prepared as follows: Amixture of 10 ml. of distilled cyclopentanone dimethyl ketal and 4.5 g.of 19-nor-B-nortestosterone with a trace of p-toluenesulfonic acid isplaced in a flask equipped with a water trap. The mixture is heated at150-175" C. bath temperature until the collection of distillate iscomplete. The residue is cooled, diluted with aqueous methanol with afew drops of pyridine then chilled to give 19-nor-B-nortestosterone 17-cyclopentenyl ether. The cyclohexenyl ether is similarly prepared usingcyclohexanone dimethyl ketal.

Another portion of 19-nor-B-nortestosterone (1 g.) is heated at refluxwith an excess of dihydropyran in benzene with a trace ofp-toluenesul-fonic acid. Concentration gives the tetrahydropyranyl etherof 19-nor-B-nortestosterone.

EXAMPLE 4 A mixture of 2 g. of 17a-methyl-19-nor-B-nortestosterone in 30ml. of methanol is mixed with a solution of 0.5 g. of sodium borohydridein ml. of water and 5 ml. of sodium hydroxide solution. After 25 minutesat room temperature water is added. The mixture is extracted withmethylene chloride. The dried solution is concentrated, ether is addedthen the mixture is concentrated again until crystallization of the17u-methyl-19- nor-B-nor-4-androstene-3,17-diol begins.

This material (1.85 g.) in 30 ml. of methylene chloride and 2.5 g. ofm-chloroperbenzoic acid is stirred for one hour then washed with water,alkali and water again. The dried organic layer is concentrated andether added to separate 17a-methyl-19-nor-B-norandrostane-3,l7-diol4,5-epoxide.

A mixture of 1.35 g. of the epoxide in 75 ml. of acetone is cooled andtreated rapidly with 2.5 ml. of Jones reagent (chromic oxide in sulfuricacid). After stirring for three minutes, 2.5 ml. of sodium bisulfitesolution is added followed by 2.5 g. of sodium bicarbonate, 5.0 g. ofsodium sulfate and 4 g. of a filter aid. The mixture is filtered. Thefiltrate is evaporated. The residue is taken up in ether, washed withwater, alkali and water. The dried solution is concentrated to give th3-ketone.

This material (900 mg.) with 20 ml. of chloroform and 2 g. of pyridinehydrochloride is stirred then refluxed overnight. The solution isevaporated to a thick oil which is taken up in ether and water. Theethereal layer is separated, washed, dried and concentrated. Theaddition of petroleum ether gives the desired4-chloro-19-nor-B-17amethyl-testosterone.

This material (1.5 g.), 125 ml. of tert.-butyl alcohol, 1.5 g. ofpotassium hydroxide and 25 ml. of water is refluxed under nitrogenovernight. Most of the alcohol is removed and water added to theresidue. Extraction with methylene chloride gives4-hydroxy-17-nor-B-n0r-17amethyl-testosterone. Acetylation at roomtemperature with acetic anhydride gives the 4-acetate derivative.

EXAMPLE 5 suspension is stirred for one hour then poured into acidicemixture, Extraction with methylene chloride gives 4-chloro-l9-nor-fi-nortestosterone acetate. Using sulfuryl bromide givesthe 4-bromo derivatives.

EXAMPLE 6 In a flask fitted with a nitrogen inlet tube is placed 20.7 g.of 3B,19-diacetoxy-5B-hydroxy-17-oxo-B-norandrostan-6-oic acid5,6-lactone and the lactone is heated at 200-205 C. for 10-12 minutes oruntil the evolution of gas has stopped. The crude product is dissolvedin 200 ml. of dry tetrahydrofuran and a solution of 248 ml. of 2 Mmethyl magnesium bromide in tetrahydrofuran-benzene is added dropwiseover one hour. The solution is heated to reflux for two hours andallowed to sit overnight. Ammonium chloride solution, then iced dilutedhydrochloric acid is used to hydrolyze the complex. The product isextracted into ethyl acetate and washed with diluted sodium bicarbonatesolution and water. Evaporation of the dried solution gives crude3,6,17/3,19-trihyrdroxy-17a-methyl-B-nor-androst-5-ene which isrecrystallized from ethyl acetate or acetonehexane to give a M.P. 196l99C. The analytical sample has a M.P. 200-202 C. [a] =139. (C=0.61% inCHCl A mixture of 10.2 g. of the trihydroxy compound, 52 ml.cyclohexanone and 310 ml. toluene is azeotroped until 250 m1. distillatehas been collected. Then 3.7 g. of finely ground aluminum isopropoxideis added and heating is continued for 4045 minutes with a slowdistillation. The reaction is quenched with 4 ml. of water, the solidsare filtered and leached with 3:1 ethyl acetatemethanol. The filtratesare concentrated to ml., cooled and the product filter giving175,19-dihydroxy-17amethyl-B-norandrost-4-ene-3-one M.P. 190196 C.Recrystallization from 1:1 acetone-methanol yields a melting point of198200 C. [a] =27.8 (C=0.497 in MEOH).

EZQ =242 my. (6 =13,300)

. once with ethyl acetate and the alkaline extracts acidified in thecold with hydrochloric acid. The aqueous solution is thoroughlyextracted with methylene chloride, the organics washed with saturatedsodium chloride solution. The solution is dried and concentrated. Thewhite crystalline l7fl-hydroxy-l7a-methyl-B nor androst-4-ene-3-one-19-oic acid was recrystallized from ethyl acetate giving a melting pointof l75l76 C. [a] =-4.85 (C=0.324 in CHC1 1 z 2u 240 m =13,400)

A solution of 2.6 g. of this compound in 26 ml. of pyridine is refluxedfor three hours. The pyridine is evaporated in vacuo and the residuedissolved in 50 ml. methanol and 5 ml. of 10% sodium hydroxide solutionthen heated on the steam bath for 10 minutes. The methanol is evaporatedand the residue triturated with water. The buff solid is washed wellwith water and recrystallized from aqueous methanol giving19-nor-l7a-methyl-B-nor testosterone with a melting point of 154156 C.[a] =60.5 (C=0.197 in CHCl ggg =239 mu (e EXAMPLE 7 A mixture of 24.0 g.of 3B,19-dihydroxy-B-nor-androst- 75 5-ene-l7-one hydrate, ml. ofcyclohexanone and 72 ml. of toluene is azeotroped over a water trap.Then about 500 ml. of toluene is distilled out of the reaction flask,gradually slowing down the rate of distillation. To this concentratedsolution is added all at once 6.0 g. of finely ground aluminumisopropoxide' and heating is continued for 15 minutes, during which timethe distillate is collected and not allowed to return to the reactionvessel. Then the temperature is adjusted to about 80 C. with an icewater bath and 6.0 ml. of water is added. After a few minutes theinorganic salts are filtered off and the filtrate steam distilled. Thecrude product is extracted into ethyl acetate, dried over sodiumsulfate, concentrated and crystallized from acetone-hexane. There isobtained 19- hydroxy-B-nor androst-4-ene-3,17-dione with a melting pointof 178-180" C.

To a solution of 8.7 g. of 19-hydroxy-B-nor-androst-4- ene-3,17-dione in160 ml. of acetone is added 24.0 ml. (0.096 mole) of standard Jonesreagent (26.7 g. chromic acid dissolved in 23 m1. of sulfuric acid anddiluted to 100 ml. with water) at C. over a period of 25 minutes. Thereddish-brown mixture is stirred an additional to minutes at 0-5 C.,then poured into 1 l. of iced brine. The crude acid is extracted intomethylene chloride (4X 250 ml.). The organic extracts are washed oncewith a little saturated sodium chloride solution, and then thoroughlyextracted with 5% sodium carbonate solution (5 X 150 ml.). The alkalineextracts are backwashed once with a little methylene chloride and thenacidified in the cold with concentrated hydrochloric acid. The liberatedacid is reextracted into methylene chloride, washed with salty water,dried (sodium sulfate) and the solvent evaporated to give a syrup whichcrystallized on standing, B- nor androst-4-ene-3,17-dione-19-oic acidhaving a melting point of 157159 C.

A solution of 9.0 g. of crude, oily B-nor-androst-4-ene-3,17-dione-19-oic acid, 160 ml. acetic acid, 300 ml. methanol and 13.5g. of Girards T reagent [see Gazzetta. Chem. Ital., 93 (5), 514 (1963)]is refluxed 0n the steam bath for two hours, then diluted with asolution of 17.8 sodium carbonate in 2 /2 1. of water (gas evolution).This solution with a pH 6-7 is extracted with ether (2x200 ml.). Theaqueous layer acidified with concentrated hydrochloric acid to pH 1 andallowed to stand at room temperature for about two hours, then extractedrepeatedly with methylene chloride. The organic extracts are washed withsalty water, dried and evaporated to give a tan solid which isrecrystallized from aqueous methanol giving 19-nor-B-nor-androst-4-ene-3,17-dione having a melting point of 1-1 3 9 in which:

R is a member selected from the group consisting of 0 OH OH OR o q q andon. H 01H; R is a member selected from the group consisting of carboxy,hydroxymethylene and acyloxymethylene;

R is a member selected from the group consisting of-keto,

fl-hydroxymethylene and B-acyloxymethylene; and the vinyl group at the4, 5 and 6 positions indicated by is at a position selected from thegroup consisting of A and A said acyl groups being derived fromcarboxylic acids having a maximum of 8 carbon atoms.

2. 3p,l9-dihydroxy-B-norandrost-5-ene-l7-one.

3. 19-hydroxy-B-norandrost-5-ene-3,17-dione.

4. B-norandrost-4-ene-3,17-dione-l9-oic acid.

5. 3B,17,3,19-trihydroxy-17a-methyl B norandrost-5- ene.

6. 17B,19-dihydroxy-17u methyl-B-norandrost-4-ene- 3-one.

7. The method of preparing a 19 carboxy B norandrostane comprisingoxidation of a 19-hydroxymethylene-B-norandrostane using the Jonesreagent.

8. The method of preparing a A -19-nor-B-norandrostene-3-one comprisingpyrolysis of a A -B-norandrostene-3-one-10-oic acid in an excess ofpyridine at reflux to form a A -l9-nor-B-norandrostene-3-one, thenrearranging said A -androstene by mild treatment with base.

9. 3B,19-diacetoxy-5,6-epoxyandrostan-17-one.

10. 35,19-diacetoxy-Sa-hydroxyandrostan-6,17-dione.

11. 3,8,l9-diacetoxy-5,l7 deoxo-5,6-secoandrostan-6- oic acid.

12. 3 8,19-diacetoxy-5 3-hydroxy-17-oxo B norandrostan-6-oic acid5,6-lactone.

13. The method of preparing l9-nor-B-norandrost-4- ene-3,17-dionecomprising reacting B-nor-androst-4-ene- 3,17-dione-19-oic acid withGirards T reagent under acid conditions then hydrolyzing the resultingGirards T intermediate by acid treatment.

No references cited. LEWIS GOTTS, Primary Examiner.

A FRENCH Assistant Examiner,

1. A COMPOUND OF THE FORMULA: